Cancer Cells Mutations
The current standard of care for cancer is a very general “one-size-fits-all” therapy.
And the more we learn about cancer the more we realize that all cancers are different and the treatment is becoming less and less realistic. The problem with chemotherapy is that it has no way to directly target cancer cells. Chemotherapy acts by killing any cell that is in the process of dividing.
Ideally, because cancer cells divide much more rapidly than normal cells, they are targeted more. However, the more we learn about the adaptability of cancer cells that enable them to evade certain therapies, combined with the fact that there are several systems of healthy cells that are also constantly dividing, we are forced to rethink the future of cancer therapies. For example, hair cells, skin cells, intestine cells, and bone marrow cells are all normal healthy cells that are constantly dividing and therefore suffer from chemotherapy. The bone marrow is where new blood cells are constantly being made (about 500 billion cells per day), this includes red and white blood cells.
This is why you see side effects like anemia, easy bruising and bleeding, (both due to low red blood cell count) decreased immune system and increased chances of infection, (due to loss of white blood cells). As well as hair loss, nausea, vomiting, appetite changes, constipation, skin and nail changes, and these are just a few of the many other side effects.
However, it’s not all bad news.
There has been a lot of research done in recent years that are helping scientists and doctors better understand cancer and come up with therapies that are more individually tailored for a patient’s needs. This starts with understanding the keys to cancer cell growth and survival. Tumor cells arise from mutations in the DNA sequences. Mutations are changes in nucleic acid sequences, chromosomal rearrangements, or aneuploidy (presence of an abnormal number of chromosomes). One property of cancer cells is this genomic instability or a high frequency of mutations within the genome of a cellular lineage. Genomic instability facilitates the escape from cytotoxic or targeted therapies.
Cancer cells have a high tolerance to DNA damage, which can be achieved by alterations of any of the 6 major DNA repair pathways (base excision repair, mismatch repair, nucleotide excision repair, translesion DNA synthesis, homologous or nonhomologous recombination). When there are constant imperfect replications, tumor cells can have different morphological (form or structure) and phenotypic (characteristics or traits) expressions.
For example, gene expression, metabolism, hormone dependence, motility, proliferation or metastatic potential, or drug resistance can all be affected. This is called clonal heterogeneity and is one of the key challenges in cancer medicine. In this case heterogeneous means that a cell doesn’t just represent one disorder but many diseases.
Not only that, but within one cancer tumor, there can be many different types of cancer cells.
Now that we’ve discussed why cancer cells are so different from one another (making non-specific therapies fairly aimless), let’s talk about some other characteristics that help them stay alive. Tumor cells thrive in and exploit cellular stress by activating an adaptive stress response pathway which leads to increased stress tolerance. An unstable environment fuels mutations and adaptations. There are three main ways (that we know of so far) that allow cancer cells to exploit cellular stress, which will be outlined and then explained in further detail. These characteristics are reversible adaptive plasticity (RAP), stress-induced dormancy, and extracellular remodeling.
A primary aspect of cancer cells is that they are extremely adaptive and evolve quickly. This is mainly due to the constant mutations explained above. Think about evolution through natural selection and speed that up hundreds of times. One adaptation is called reversible adaptive plasticity (RAP).
This means that cancer cells have the ability to switch growth patterns between proliferation anchorage-dependent (meaning the cells have to adhere somewhere to proliferate) or slow-growing independent anchorage (meaning they don’t need to adhere to divide). Anchorage dependent cells are more sensitive to chemotherapy where anchorage-independent cells are less sensitive or completely resistant. When chemo is introduced to the body it can trigger this RAP response to allow cancer cells to become more resistant.
The second characteristic is called stress-induced dormancy. This is also known as transient growth arrest, meaning cells can enter a stage of dormancy to survive hostile environments. Cellular dormancy is caused by angiogenic or immunogenic factors that have direct growth inhibitory effects on tumor cells. By entering a state of dormancy, tumor cells temporarily stop replicating and therefore are no longer targets of chemotherapy.
Another way they handle stress is by extracellular matrix remodeling.
Extracellular remodeling is a complex chain of molecular and cellular events where cancer cells can actively remodel the microenvironment, by secreting factors, locally to relieve stress and systemically to fuel malignant growth. In order for metastasization to occur a secondary organ must be actively altered in some way to provide a hospitable environment for cancer cells, which does not happen passively. This will alter the structure of the secondary organ in order to allow cells to more easily travel to and colonize, therefore forming a secondary tumor. This phenomenon is called the pre-metastatic niche.
All this changing and adapting means that cancer you treat today may be different than cancer you treat in two weeks from now. It may have taken the stressful environment induced by chemotherapy and evolved to better evade being killed by the second round of chemotherapy.
Also, since everyone’s DNA is different, two people with bladder cancer may respond completely differently to the same treatment. It may seem dismal however knowledge is power and the more we learn about cancer the closer we come to finding a solution. Researchers believe that in the future, chemo will no longer be the main therapeutic response but that we will have established more individualized and specific therapies.